title: Co-application of the GABAB receptor agonist, baclofen, and the mGlu receptor agonist, L-CCG-I, facilitates [(3)H]GABA release from rat cortical nerve endings.
abstract: Interaction between different transmitter receptor systems is an emerging feature of neurotransmission at central synapses. G protein-coupled receptors' ability to form dimers or larger hetero-oligomers probably serves to facilitate the integration of diverse signals within the cell. We found that, in nerve terminals isolated from the cerebral cortices of rats, co-application of the GABAB agonist, baclofen, and of the non-selective mGlu agonist, L-CCG-I, potentiates the basal and depolarization-evoked release of [(3)H]GABA via a mechanism that involves mobilization of intracellular Ca(2+) ions. The effect of L-CCG-I + baclofen was abolished by the phospholipase C inhibitor U73122, reduced by Xestospongin C (an IP3 receptor blocker), and blocked by 2-APB, an IP3 receptor antagonist. Pretreatment of the synaptosomes with the lipid-soluble Ca(2+) chelator BAPTA-AM also inhibited the effects of L-CCG-I + baclofen. Subtype-selective non-competitive group I mGlu receptor antagonists, MPEP and CPCCOEt, had no effect on the release enhancement produced by baclofen + L-CCG-I. The enhancement was reversed by the GABAB receptor antagonist, CGP54626, and by the group I/group II mGlu receptor antagonist (R,S)-MCPG. The GABA release-enhancing effects of L-CCG-I + baclofen in our model might reflect the presence on cortical nerve endings of GABAB/group I mGlu receptor heteromers with pharmacological properties distinct from those of the component receptors. Activation of these heteromeric receptors might modify the function of the GABAB receptor in such a way that it facilitates GABAergic transmission, an effect that might be useful under conditions of excessive glutamatergic activity.
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, Catholic University of Sacred Heart, Largo F. Vito 1, 00168, Rome, Italy.
authors.forename: Irene A
authors.initials: IA
authors.lastname: Samengo
authors.forename: Valerio
authors.initials: V
authors.lastname: Scotti
authors.forename: Maria
authors.initials: M
authors.lastname: Martire
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000648:ultrastructure; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000600:Amino Acids, Dicarboxylic; D002614:Chelating Agents; D004963:Estrenes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D009943:Organophosphorus Compounds; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C107353:CGP 54626; C035261:(alpha-carboxycyclopropyl)glycine; D005680:gamma-Aminobutyric Acid; D001418:Baclofen